Vol 25, No 2 (2022)

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Full Issue


On the relationship between anosmia/dysgeusia and nonspecific immunoprophylaxis COVID-19

Berdyugina O.V., Gusev E.Y.


The issues of non-specific immunoprophylaxis in the patients with new coronavirus infection have been raised since the WHO announced the COVID-19 pandemic. According to numerous studies, the new coronavirus infection is accompanied by manifestations of anosmia and dysgeusia. The purpose of this study was to perform a retrospective study of the relationships between nonspecific immunoprophylaxis of COVID-19 and conditions of anosmia/dysgeusia in the persons who underwent this infection in Sverdlovsk region over 2020.

We have studied clinical and laboratory data of 84 employees at the general medical institution providing emergency pediatric care. All participants suffered a single infection caused by SARS-CoV-2. Etiological diagnostics included mandatory virological PCR testing of biological samples. The concentration of antibodies to the virus was determined using a set of reagents for SARS-CoV-2-IgG detection (JSC Vector-Best, Novosibirsk, Russia). A sufficient part of this group (n = 41; 48.8% of total sample) reported self-administration of non-specific immunoprophylactic therapy of COVID-19 (without consulting a doctor) since the beginning of coronavirus pandemics. To this purpose, cholecalciferol, riamilovir, human recombinant IFNa-2b, umifenovir hydrochloride monohydrate, ascorbic acid, zinc acetate were used. In 58 cases (69% of total), clinical course of infection was complicated by loss of taste and sense of smell (group No. 1), in 26 people (31.0%), no changes in taste and sense of smell were detected (group No. 2). Statistical evaluation of the data was performed using STATISTICA v. package (StatSoft, Inc., USA). Along with basic statistics, cluster analysis was performed.

The use of cluster analysis allowed us to establish that there is a connection between the incidence of anosmia/dysgeusia and usage of distinct immunoprophylactic agents. In particular, the use of human recombinant IFNa-2b is protective in terms of reducing the number complications in COVID-19, especially, anosmia/dysgeusia caused by the new coronavirus. The use of this drug was associated with 8.5-fold decrease in the number of complications by (p = 0.03). Moreover, invasive intranasal usage of interferon, was associated with decreased hospitalization terms by 14.3% (p = 0.01); lower volume of lung tissue damage (p = 0.03), higher concentrations of IgG to SARS-CoV-2 at 2 months after reconvalescence (p = 0.001).

For the first time, data were presented on the relationship between usage of immunoprophylactic agents and manifestations of anosmia/dysgeusia in COVID-19. The protective role of human recombinant IFNa-2b has been shown in terms of reduced incidence of the disease complications, e.g., anosmia/dysgeusia, degree of lung damage, as well as development of an antiviral humoral immune response. The data obtained could be used to substantiate clinical recommendations for prevention of new outbreaks of coronavirus infection. The limitation of the obtained results is small number of cases, thus requiring additional studies in a wider sample of respondents.

Russian Journal of Immunology. 2022;25(2):117-124
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Relationships between cytokines and the amounts of microsymbionts in microecological disorders of the human intestine

Bondarenko T.A., Ivanova E.V., Bekpergenova A.V., Chaynikova I.N., Chelpachenko O.E., Nikiforov I.A., Zdvizhkova I.A.


Cytokines and chemokines, as well as gut microsymbionts, are sufficient participants in the intercellular communications, thus supporting homeostasis of gut mucosa. However, these components may be of key significance for intestinal inflammation and damage to epithelial barrier. This work expands the understanding of the relationships between intestinal microbial communities and the local cytokine network of the host. The paper presents the results of the correlation analysis between total microbial number of intestinal microsymbionts and the level of pro- (TNFα, IFNγ, IL-8) and anti-inflammatory cytokines (IL-10, IL- 1ra) in coprofiltrates obtained from clinically healthy people examined for gut dysbiosis. Determination of cytokines in coprofiltrates was carried out by ELISA technique (JSC Vector-Best, Russia). The study of 65 microsymbiocenoses of the human gut was carried out by classical bacteriological methods. Identification of obligate-anaerobic, facultative-anaerobic bacteria and fungi was carried out by time-of-flight mass spectrometry using MALDI TOF-MS Microflex LT series (Bruker Daltonians, Germany). These studies have revealed the leading role of associations between enterobacteria, fungi and representatives of the Staphylococcus genus in gut dysbiosis. In general composition of the obligate-anaerobic association, we have observed a change of consortia from several types of Bifidobacteria and Lactobacilli in eubiotic state to a monoid variant in dysbiosis. At the same time, the number of associations that included Clostridia was increased. The analysis of correlations between cytokine indices and the number of gut microbiota showed persistance of significant associations established during eubiosis under dysbiosis conditions, with an increase in their correlation coefficient: Bifidobacterium spp., Enterobacteriaceae, Staphylococcus spp., Candida spp. and TNFα. At the same time, in dysbiosis, the direction of the connections changed, and new correlations were determined: for Staphylococcus spp. and IFNγ; Staphylococcus spp. and IL-8; Enterobacteriaceae and IL-1ra, IFNγ. The established features of correlations between indices of microsymbiocenosis and quantitative changes in cytokines allow us to consider the number, composition of microsymbiocenosis and cytokine profile as factors that may affect the state of gut homeostasis in eu- and dysbiosis.

Russian Journal of Immunology. 2022;25(2):125-130
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Cellular immune response to DNA vaccine encoding receptor-binding domain of SARS-CoV-2 S protein: dependence on the packing mode

Borgoyakova M.B., Karpenko L.I., Starostina E.V., Volosnikova E.A., Zadorozhny A.M., Orlova L.A., Ilyichev A.A.


Massive vaccination against SARS-CoV-2 appears to be one of the most important steps towards solving the problem of the COVID-19 pandemic, which threatened the lives of millions of people over two and a half years. To create anti-COVID-19 vaccines, both traditional approaches (inactivated vaccines), and innovative efforts were used, including the nucleic acid-based vaccines (mRNA, DNA vaccines) which appeared on the market. We constructed a plasmid (DNA vaccine) encoding the gene for the receptor-binding domain (RBD) of spike protein (S) of the SARS-CoV-2 virus. This DNA vaccine was named pVAXrbd. The polycationic carrier polyglucin-spermidine (PGS) and its recombinant RBD protein conjugate (PGS-RBD) were used to package pVAXrbd. By adding the negatively charged DNA pVAXrbd plasmid to polycationic PGS or PGS-RBD molecules, the complexes of polymers with plasmid DNA were formed by self-assembly, due to their non-covalent interaction. The aim of this work was to study cellular response induced by the DNA vaccine at various packaging options, as well as to analyze influence of the vaccine packaging upon development of the immune response. BALB/c mice were injected with DNA vaccine in three versions: “naked” pVAXrbd; plasmid pVAXrbd in PGS envelope; pVAXrbd in PGS-RBD wrapper. In control group, the animals were injected with the recombinant RBD protein. Cellular response was assessed by the IFNγ production using two methods, i.e., ELISpot and ICS using flow cytometry. It was shown that the DNA vaccine pVAXrbd, both per se, or as part of complexes, showed the ability to induce cellular immune response. The most effective cellular immune response was found in the group of animals immunized with pVAXrbd-PGS complex. Using ELISpot detection technique for this group, the largest number of cells responding by IFNγ release was registered upon stimulation with specific peptides; usage of ICS and flow cytometry for evaluation in this group showed higher percentage of IFNγ-producing CD4+ and CD8+T cells. This observed effect could be explained by DNA protection from nuclease action by the polyglucin-spermidine envelope. The pVAXrbd-PGS complexes may be also more efficiently recognized by antigen-presenting cells than naked plasmid DNA. The presented results show that the polyglucin-spermidine envelope provides an increase in immunogenicity of the DNA vaccine pVAXrbd, in terms of virus-specific T cell response.

Russian Journal of Immunology. 2022;25(2):131-138
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Frequency and parameters of linkage disequilibrium of the two-locus HLA-B~MICA haplotypes in russians from chelyabinsk region

Vavilov M.N., Suslova T.A., Burmistrova A.L.


MICA gene is located in the MHC region on chromosome 6p21.33, mapped ca. 46.4 kb centromeric to the HLA-B gene, being in strict linkage disequilibrium with MHC class I region. The sufficient polymorphism of human MICA gene and its location at the HLA region makes it a likely candidate locus for additional histocompatibility testing. The data on distribution of two-locus HLA-B~MICA haplotypes enable us to obtain information about the level of mismatches in the MICA locus when selecting suitable donor-recipient pair by convential HLA loci for unrelated hematopoietic stem cell transplantation. We have performed immunogenetic typing of 100 donors of Russian Nationality from the Register of Stem Cell Donors at Chelyabinsk Regional Blood Bank. MICA genotyping was carried out by PCR tests with sequence-specific primers at basic resolution. Typing of the classical HLA-B locus was carried out by the NGS method using MiSeq instrument using a MiSeq v2 reagent kit (Illumina). Linkage disequilibrium indices D, D`, p, and the frequency of two-locus HLA-B~MICA haplotypes were calculated using Arlequin 3.5 software. As a result of this study, the main parameters of linkage disequilibrium and the frequency of two-locus HLA-B~MICA haplotypes were established for Russians from the Chelyabinsk region. HLA-B allelic groups have been identified that form stable pairs with specific MICA allelic variants (HLA-B*B*07, B*08, B*13, B*14, B* 27, B*37, B*38, B*47, B *48, B*49, B*50, B*52, B*55, B*56, B*57). Moreover, we have revealed HLA-B allelic groups forming highly variable HLA-B~MICA haplotypes (HLA-B*15, B*18, B*35, B*39, B*40, B*41, B*44 and B*51) with increased risk of mismatch for MICA genes. These results could be used in clinical practice in order to assess probability of the donor/recipient mismatch for non-classic MICA locus when selecting potential stem cell donors for hematological patients by HLA testing of classical loci. Moreover, these data could be demanded in population genetics.

Russian Journal of Immunology. 2022;25(2):139-146
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Plasma extracellular DNA and neutrophilic leukocyte activity in patients with rheumatoid arthritis

Gavrilova E.D., Demchenko E.N., Goiman E.V., Chumasova O.A., Volskiy N.N., Sizikov A.E., Kozlov V.A.


Neutrophilic leukocytes play a key role for the joint damage in development of rheumatoid arthritis (RA). The specific death mode of these cells (netosis) may be an important reason of increase of cell-free DNA (cfDNA) in peripheral blood of the RA patients. Of great interest would be studies of alleged relationships between the of blood cfDNA contents being able of playing the role of an auto-antigen participating in the initiation of autoimmune reactions, and indices of neutrophil activation in this immunopathological disorder. The aim of the present study was to determine the levels of cfDNA in blood plasma of patients with RA depending on the clinical course of the disease, and to evaluate possible relationships between this index and activation of neutrophilic leukocytes. The study was conducted on 28 conditionally healthy donors and 63 patients with RA from the Rheumatology Department at the Clinic of Immunopathology (Novosibirsk). The level of cfDNA was determined using PicoGreen fluorescent dye. Neutrophils from the peripheral blood of donors and patients with rheumatoid arthritis were isolated in a Ficoll-Urografin density gradient. Neutrophilic leukocytes accounted for more than 98% of the fraction of isolated cells, and their viability was 99%. A portion of freshly isolated neutrophils was stimulated by phorbol myristate acetate. Concentration of myeloperoxidase in blood plasma of donors and patients with RA was determined using the Human MPO ELISA kit. It has been shown that the increased concentration of extracellular DNA in blood plasma of RA patients correlates with an higher degree of disease activity, and this parameter may serve as a relatively independent indicator of the disease intensity. A correlation was found between the level of cfDNA and common biochemical markers used to assess the activity of disease, i.e., DAS-28 and C-reactive protein levels in serum (p < 0.05). Decrease of cfDNA concentrations is detected during treatment of the RA patients. This is due to the expected prognosis, i.e., a decreased manifestation of the disease, which also means correct administration of therapy. A relationship was found between the level of cfDNA and blood myeloperoxidase concentration in RA patients. The data obtained during the study suggest a possible connection between increased concentration of extracellular DNA, and activation of neutrophilic leukocytes in rheumatoid arthritis, with increased netosis in the affected joints.

Russian Journal of Immunology. 2022;25(2):147-154
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Human endogenous retrovirus HERV-E λ 4-1 in immunopathogenesis of affective disorder

Goldina I.A., Goldin B.G., Markova E.V.


The aim of this work was to study a dependence between the production level of some pro-inflammatory cytokines by peripheral blood mononuclear cells, and activation of human endogenous retrovirus HERV-E λ 4-1 in the patients with recurrent depression. Patients and methods: the study included 30 patients with an verified diagnosis of recurrent depression (F 33.0) aged 26-45 years, with a disease duration of at least 3 months prior to inclusion into the study. Peripheral blood mononuclear cells were isolated by centrifugation in Ficoll density gradient (1.078 g/cm3). The human endogenous retrovirus HERV-E λ 4-1 env gene expression was determined by polymerase chain reaction using paired oligonucleotide primers. To assess the cytokine production, peripheral blood mononuclear cells were cultured for 24-72 hours, depending on the experimental conditions. Quantitative determination of spontaneous cytokine production was carried out by a “sandwich” variant of ELISA method in conditioned media from the cell cultures, according to the manufacturer instructions. Results: our data reveal higher production of IL-1β and IFNγ in peripheral blood mononuclear cells from those patients with recurrent depression who showed detectable HERV-E λ 4-1 env expression compared to the patients in whom the HERV-E λ 4-1 env gene expression was not detected. When studying correlation between HERV-E λ 4-1 env expression and production of IL-1β and IFNγ, a positive correlation between the studied parameters was established. Thus, taking into account our earlier data on HERV-E λ 4-1 immunomodulatory properties, as well as literature data concerning the HERV transcripts found in brains of mentally ill patients, along with increase of IL-1β and IFNγ production in the patients with recurrent depression and positive HERV-E λ 4-1 env gene expression, and a positive correlation between the HERV-E λ 4-1 env gene expression and increased level of cytokines involved in formation of pathological events in the nervous system in the patients with depression, one may conclude that activation of HERV-E λ 4-1 could participate in immunopathogenesis of recurrent depression by stimulating the synthesis of pro-inflammatory cytokines.

Russian Journal of Immunology. 2022;25(2):155-160
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Impairment of natural killer populations in the patients recovered from COVID-19

Dobrynina M.A., Zurochka A.V., Komelkova M.V., Luo S.


To date, only minimal attention has been paid to assessment of immunity state in patients with post-COVID syndrome. Influence of the SARS-CoV-2 virus on various systems in the body, including the immune system, may contribute to the development of disorders causing different diseases. At the same time, the patients suffering from the COVID-19 complications, including hospitalization and isolation from their family members, experience severe psychological and social stress. In almost every fourth case, these factors lead to development of the s.c. post-COVID syndrome. The aim of the present study was to evaluate the numbers of NK cells, levels of cortisol and characteristics of immune system disorders in the patients who underwent SARS-CoV-2 infection.

78 patients were examined 6 months after suffering COVID-19. We have assessed 25 parameters of the blood system (general blood test), 50 parameters of immune system, i.e., counts of T lymphocytes, B lymphocytes and their functional markers, NK, T-NK cell subsets, phagocytic components of immune system, as well as factors of humoral immunity, including total and specific immunoglobulins and complement fragments.

Our studies showed a sharp, three-fold decrease in the number of natural killers in more than 1/3 of the examined individuals. This decrease is accompanied by higher relative contents of T lymphocytes and T helper cells. The latter finding may be associated with a compensatory increase in T lymphocytes and dysregulation of the T cell link of immune system, thus requiring a more detailed study and, most likely, evaluation of the cytokine profile in such patients. Moreover, in some post-COVID patients, high levels of cortisol still persist, thus suggesting maintenance of chronic stress in these patients. Some changes in platelet counts are also important (increased levels of blood platelets and thrombocytocrit), which may promote later disorders of blood clotting system and development of thrombosis.

Russian Journal of Immunology. 2022;25(2):161-166
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First experience in usage of lipoaspirate-derived mesenchymal stromal cells in combined treatment of the patients with liver cirrhosis

Zheltova O.I., Shevela Y.Y., Meledina I.V., Chernykh E.R.


Liver cirrhosis (LC) is a serious problem with respect to drug therapy. Certain promises are associated with development of stem cell-based technologies, in particular, mesenchymal stromal cells (MSCs). Over recent years, a significant interest was drawn to the usage of MSCs isolated from adipose tissue, which have a number of advantages over bone marrow MSCs. The aim of this study was to evaluate safety and tolerability of transplantation of autologous MSCs derived from adipose tissue (lipoaspirate) when treating the patients with LC of different origin. The study group consisted of 12 patients (4 men and 8 women), aged 33 to 67 years. In six patients, development of LC was due to viral hepatitis; in other subjects it was caused by non-viral factors, including toxic effects (n = 3), primary biliary cirrhosis (n = 2) and cryptogenic cirrhosis (n = 1). The LC severity assessed by the Child-Pugh scale corresponded to class A (6 cases) or class B (6 patients). The MELD scores varied from 8 to 11. All patients were injected once with autologous MSCs (a mean of 12.94 × 106, 11.3 to 16.0 × 106) obtained by culturing the lipoaspirate cells for 14 days. Lipoaspiration and injection of MSCs were not accompanied by development of side effects, or serious adverse events. Analysis of clinical efficacy, carried out 6-12 months after therapy, made it possible to distinguish two subgroups: responders to the therapy (subgroup 1, n = 6) and non-responders (subgroup 2, n = 6). In subgroup 1, the MELD score was found to be decreased in 4 cases, and did not change in 2 patients. In contrast, the MELD score increased in the patients from subgroup 2. Both subgroups did not differ in etiology and severity of LC, or concomitant pathology (COVID-19). Positive dynamics in subgroup 1 was revealed for the signs of hepatocellular insufficiency (n = 1), cytolysis (n = 2) and cholestasis (n = 1). In two patients with MELD score stabilization, the scores reached the reference values. After MSC therapy, the majority of patients (8/12) underwent a new coronavirus infection, and the COVID incidence rate was similar in groups with or without response to MSC therapy (4 patients in each group). The results of the study suggest the safety of using MSCs isolated from the adipose tissue of patients with liver cirrhosis, and the perspectives of such approach in order to stabilize or improve liver function.

Russian Journal of Immunology. 2022;25(2):167-172
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Diagnostic efficacy of C-reactive protein and IL-6 as markers of systemic inflammation

Zhuravleva Y.A., Zotova N.V., Solomatina L.V.


Currently, despite widespread use of the terms “systemic inflammation” (SI) and “systemic inflammatory response” (SIR), there are no generally accepted criteria for their verification. These processes are often identified (which is methodologically incorrect) and associated with an increase in pro-inflammatory mediators in the blood. However, SI is a complex process that requires integral criteria including assessment of SIR as reactivity level, and additional SI phenomena, such as microthrombosis, systemic alteration, and distress of the neuroendocrine system. At the same time, there is a need to assess individual CB indicators as a more affordable alternative for medical practice than the use of complex integral indicators. Our objective was to evaluate diagnostic efficacy of CRP and IL-6 levels as markers of acute and chronic systemic inflammation.

The data of patients with acute critical conditions of infectious and non-infectious genesis were analyzed to study acute systemic inflammation (SI), data of patients with autoimmune diseases, chronic organ failure and other chronic destructive diseases were analyzed to study chronic systemic inflammation (ChrSI). SIR severity was evaluated by the calculation of an integral index – reactivity level (RL). Differentiation of the inflammatory process to either classical inflammation (CI), or systemic inflammation was carried out using the previously proposed scale of SI, verification of chronic systemic inflammation was performed by means of ChrSI scale. SI (or ChrSI) was revealed in all groups of patients, and the frequency of SI registration in patients with acute conditions increased with development of multi-organ failure. The frequency of SIR was higher in all groups, thus confirming inability to equate these disorders. ROC analysis showed that CRP level had poor diagnostic efficacy on the development of SI/ChrSI (AUC < 0.6), and IL-6 level had very good diagnostic value (AUC 0.8-0.9). The prognostic value of the markers for detecting the SIR was higher, with AUCIL-6 exceeding AUCCRP. Thus, IL-6 in many acute and chronic pathologies is sufficiently closer to integral indices than C-reactive protein with respect to diagnostic efficiency, and the dynamics of IL-6 in blood may be used to predict and evaluate complications associated with acute and chronic SI, as well as to prescribe and monitor the results of anticytokine therapy.

Russian Journal of Immunology. 2022;25(2):173-180
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Type III interferons in community-acquired pneumonia in children

Iziurova N.V., Savochkina A.Y., Uzunova A.N., Nikushkina K.V.


The relevance of community-acquired pneumonia is due to its widespread prevalence in pediatric practice, due to high level of morbidity and mortality in this pathological condition. Anti-infectious protection is of great importance in prevention of community-acquired pneumonia, primarily, the state of innate immunity, including cellular and humoral immune response. Among the factors of innate immunity, cytokines play an important role, being the most important mediators that control and regulate immune and inflammatory responses via complex networks and serve as biomarkers of many diseases. A single cytokine may be secreted by different cells and exhibit both pro-inflammatory and anti-inflammatory activity, depending on its context, thus causing multiple immune responses. Among cytokines, interferons play a significant role, being among sufficient factors of innate immunity. The study determined the level of type III interferons (IFNλ2 (IL-28A) and IFNλ3 (IL-28B)) in blood serum of 117 children with community-acquired pneumonia aged 1 to 18 years with an X-ray confirmed diagnosis of community-acquired pneumonia, hospitalized at the Departments of Respiratory Infections at the Pediatric Clinical Hospitals No. 7 and 8 in Chelyabinsk. All children were represented by 3 age groups, according to the generally accepted critical periods of immune system maturation, i.e., 1 to 3 years old; 4 to 7, and 8 to 18 years old. The comparison group was recruited during routine medical examination of healthy children and consisted of 28 subjects who did not show any signs of acute respiratory viral infection at the time of examination, and had no detectable chronic diseases. The purpose of this study was to determine the concentration of type III interferons in blood serum of children with community-acquired pneumonia at different ages, and to assess changes in indices, depending on the severity of the disease. According to the results of the study, we have revealed that the serum concentrations of type III interferons, in particular, IFNλ2 (IL-28A) and IFNλ3 (IL-28B) among the children with community-acquired pneumonia, were significantly higher in the subgroup of children with severe pneumonia. Significant differences in concentrations of type III interferons were shown for the children in different age groups, which may be due to peculiar features of immune system activation at different age periods and immaturity of immune system in children.

Russian Journal of Immunology. 2022;25(2):181-186
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Humoral immunity in reconvalescents and persons vaccinated against COVID-19: a comparative assessment of the main indices of the humoral immune response

Karimov I.F., Korneev A.G., Borisov S.D., Nosyreva S.Y., Ushakova A.A., Pankova A.A., Pankov A.S.


Specific humoral immunity to SARS-CoV-2 develops due to the formation of neutralizing IgG, which can primarily block the receptor-binding domain of the viral S-protein. The duration of post-infection immunity, as well as avidity of circulating antibodies, play an important role in this process. The aim of this work was to evaluate the amounts of antibodies to SARS-CoV 2 S-protein, their avidity and neutralizing activity in the studied samples of the post-COVID patients versus vaccinated seropositive individuals. Materials and methods. A sample of 113 individuals was studied, which consisted of three experimental groups, i.e.: recovered, vaccinated, as well as recovered and vaccinated persons. Blood serum specimens of the individuals were studied for specific IgG to SARS-CoV-2, along with determination of their quantities (BAU/mL) using Vector-Best kits (Novosibirsk, Russia). The avidity index was determined using a kit manufactured by MedipalTech (Dubna, Russia). Neutralizing ability of the antibodies was assayed by means of ELISA with diagnostic kits from MedipalTech (Dubna, Russia), which resulted into percentage of neutralized S-proteins to RBD. Results. The average levels of IgG did not show significant differences between reconvalescents and vaccinated persons. However, both indicators were significantly lower than those from the groups who recovered from the disease and were vaccinated. A cyclic change in the numbers of antibodies was observed, along with most intensive drop in the level of immunoglobulins over first four months after the illness or vaccination. Despite initially similar levels of immune parameters in both groups, the decline of this index in “vaccinated” group was significantly higher than in the “recovered” group, thus allowing us to conclude that the amounts of specific antibodies in this group was shown to be decreased to zero levels as soon as by the 10th month. IgG index among the «recovered and vaccinated» groups remained unchanged for the entire anamnestic period. Avidity index of the antibodies in vaccinated individuals was higher than in recovered individuals. Meanwhile, this index in both groups was characterized by stable increase over the observation period of 7 to 11 months. The highest levels of antibodies and their avidity were noted in the group of recovered and vaccinated individuals, due to the most complete activation of the immune system. A straight-line trend was revealed for the decreasing index of neutralizing activity during the considered time period. The overall pattern of thee results shows that the neutralizing activity of antibodies is largely determined by the amounts of SARS-CoV-2-specific immunoglobulins. Thus, the time dynamics of antibodies to SARS-CoV-2 in various groups of examined individuals was revealed. Direct correlation was established between the neutralizing activity and amounts of immunoglobulins, as well as the role of vaccination for increased avidity of antibodies.

Russian Journal of Immunology. 2022;25(2):187-194
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Expression of chemotaxis in regulators of tissues of exudative lesions of Reinke’s space

Kovalev M.A., Davydovа E.V.


Exudative tumor-like neoplasms of the Reinke space in vocal folds are widespread in the population, more often among representatives of vocal professions, e.g., actors, singers, teachers, lecturers and represent a serious medical and social problem. In pathogenesis of such neoplasms, a key role is given to chronic phonotrauma, intoxication during smoking against the background of the nearly complete absence of lymphatic drainage in the Reinke space. Cellular factors of tissue and immune homeostasis are of great importance in morphogenesis of this disorder. Switching of immune responses aimed at maintaining tissue homeostasis is accompanied by increased production of pro-inflammatory cytokines, as well as chemotaxis regulators and growth factors. The aim of our work was to study the levels of chemokines (MIP-1α, MIP-1β, MIP-3α, fractalkine, IL-8, I-TAC) in the tissues of exudative lesions from the Reinke’s space (EPPR).

Forty tissue samples of exudative lesions from Reinke’s space, in particular, vocal fold polyps, vocal nodules and neoplasms presenting as Reinke’s edema were taken as biological material for the study. The samples were taken intraoperatively when the neoplasm was removed, using an Olympus TYPE 150 fiber bronchoscope (Germany) using an integrated Lumenis Acu Pulse CO2 laser (Israel). The content of chemokines was determined in the supernatants of the tissues homogenates, using multiplex analysis with MAGPIX-100 immunoanalyzer (Bio-Rad, USA). Statistical processing was carried out using Statistica 10.0 for Windows software package. The results are presented as medians (Q0.25-Q0.75).

Chronic phonotrauma and/or exposure to toxic factors leads to increased permeability of the vascular endothelium, tissue edema and activation of cells involved in tissue and immune homeostasis, e.g., fibroblasts, monocytes, endotheliocytes. The study of the chemokine expression in the tissues of various exudative lesions of Reinke’s space enabled us to reveal the following features: (1) predominance of the CXC-chemokine content produced mainly by fibroblasts in “dense” neoplastic tissues, thus reflecting participation of the latter in the genesis of this pathology. (2) In the tissues of “soft” neoplasms with large proportion of liquid component, we have revealed increased concentrations of SS-chemokines and fractalkine. The latters are produced mainly by macrophages and endotheliocytes, thus, probably, reflecting a predominant role of these cells in development of myxoid polyps and Reinke’s edema.

Russian Journal of Immunology. 2022;25(2):195-200
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Distinct indexes of immunological reactivity in surgical alteration of ORL organs

Korkmazov M.Y., Dubinets I.D., Lengina M.A., Korkmazov A.M., Kornova N.V., Ryabenko Y.I.


The data are provided on applications of optical radiation at various spectral ranges in the treatment of disorders of ORL organs. Some issues of pathophysiological and immune changes of nasal mucosa in response to surgical alteration are considered for the early postoperative period. In order to increase efficiency of postoperative rehabilitation in the patients subjected to rhinosurgical interventions, we have used low-frequency ultrasonic cavitation in combination with photochromotherapy in complex treatment schedules. Assessment of clinical and immunological effects of this treatment was performed as based on the study of clinical and functional pattern at the early stages of postoperative period and stabilization of the cytokine profile. In general, an opportunity of using optical radiation at different wavelength was confirmed, as shown by studies of physical characteristics of light irradiation, explaining the mechanisms of action on the damaged mucous membrane, to apply inflammatory response to surgical trauma and restore immunological abnormalities. The work was carried out in order to draw attention to the non-drug methods of early rehabilitation of persons subjected to rhinosurgical interventions.

Russian Journal of Immunology. 2022;25(2):201-206
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Flow cytometry assessment of mitochondrial indices in CD4+T cells from peripheral blood

Korolevskaya L.B., Saidakova E.V., Shmagel K.V.


Mitochondria play a key role in the vital functions of the cell, i.e., energy production, metabolism, respiration, generation of reactive oxygen species, cell division and death. Impairment of these mitochondrial functions is associated with emergence of various diseases. Their amounts and membrane potential are important indices of the mitochondrial condition. To assess these parameters, various fluorochrome-labeled probes are used, which are detectable by flow cytometry. The opportunity of using fluorescent mitochondrial dyes, together with labeled monoclonal antibodies, opens up new prospects for studying the metabolic parameters in various immune cells. The aim of the present study was to assess the mitochondrial state in CD4+T lymphocytes by flow cytometry. To search for the differences in mitochondrial indexes, a group of HIV-infected patients receiving antiretroviral therapy (n = 21) and healthy volunteers (n = 23) were compared. Mononuclear cells isolated from peripheral blood were under the study. Using flow cytometry and commercial mitochondria-selective dyes MitoTracker Green and MitoTracker Orange, we determined, respectively, the mitochondrial mass and membrane charge in the total CD4+T lymphocyte pool, as well as in the naive and memory cell subsets. It has been shown that the mitochondrial mass and charge in naive CD4+T lymphocytes are lower than in memory cells, both in HIV-infected and uninfected subjects. Moreover, we have established that the HIV-infected patients have an increased mitochondrial mass in total CD4+T lymphocyte pool and in their memory cell subset, as compared with healthy donors. That increase, however, was not accompanied by the higher membrane charge. Thus, the analysis of mitochondrial mass and membrane potential using flow cytometry and MitoTracker Green/MitoTracker Orange dyes is relatively easy, fast, and informative for preliminary assessment of the mitochondrial state.

Russian Journal of Immunology. 2022;25(2):207-212
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In vitro evaluation of immunomodulatory activity of Bifidobacterium bifidum 791 in the cell model of innate and adaptive immunity

Kostolomova E.G., Timokhina T.K., Perunova N.B., Polyanskikh E.D., Sakharov R.A., Komarova A.V.


Over recent decades, multiple data were accumulated on immunotropic activity of Bifidum flora, based on effects of these bacteria on isolated lymphoid follicles, dendritic cells, B-cell aggregates, pro- and anti-inflammatory cytokines and chemokines, as well as participation of bifidoflora in the recognition of “non-self” during the development of microsymbiocenosis. The relevance of research in the field is associated both with fundamental issues of human host/microbiota symbiosis, but also with the prospects of practical application of the knowledge gained towards design of probiotics that affect the immune system. This article presents the results concerning effects of supernatant and bacterial cells of Bifidobacterium bifidum 791 (B. bifidum 791) strain in the model of human peripheral blood mononuclear cells (MNCs). We used the reference strain B. bifidum 791 (Russian Collection of Industrial Microorganisms from the GosNII Genetika Federal State Enterprise, Deposition No. AS-1247), which is used in production of the probiotic drug “Bifidumbacterin” (CJSC Ecopolis, Kovrov). Mononuclear cells (MNCs) were isolated from peripheral blood of 20 healthy donors. MNCs were stained with monoclonal antibodies for CD4, CD8, CD3, CD25, CD69, CD56 (Beckman Coulter, USA). Analysis of the cellular subsets was performed by multicolor flow cytometry with Cytomics FC500 instrument (Beckman Coulter, USA). The experiments were carried out in duplicate. The studies have shown that probiotic strains have an activating and modulating effect upon immunocompetent cells. The studied B. bifidum 791 strain had an immunomodulatory effect on the cells of nonspecific and adaptive immunity: it increased the percentage of CD69+ cells in the subpopulation of CD3+CD8+T lymphocytes, CD69 (%) and CD25 (%) NK cells, and promoted activation of cytotoxic lymphocytes. The supernatant of bifidobacteria had a more pronounced effect on MNCs. E.g., it increased the expression of CD69 by Th cells, induced the expression of CD25 by T cytotoxic cells, and increased the CD69 and CD25 expression (%) by NK cells compared to B. bifidum 791 bacterial cells. These data contribute to understanding the mechanisms of immunoregulatory influence of normobiota (in the Bifidobacteria models) by formation of symbiotic interactions “microbiota – host” and contribute to the development of a new research area, i.e., “infectious symbiology”. Further study of immunomodulatory activity of bifidoflora has the prospectives of searching and selection of Bifidobacteria strains, in order to create new targeted probiotic preparations.

Russian Journal of Immunology. 2022;25(2):213-218
pages 213-218 views

Dynamics of changes in the number of SARS-CoV-2 seropositive patients over two years of the COVID-19 pandemic

Kritsky I.S., Zurochka V.A., Hu D., Sarapultsev A.P.


Serological assays, being rapid and relatively inexpensive methods for detecting COVID-19, may play an important role in combating the SARS-CoV-2 pandemic. The aim of the present study was to assess dynamics of changes in the number of seropositive patients for SARS-CoV-2 antibodies over 2.5 years of the evolving COVID-19 pandemic. The study included 6051 persons (2840 women and 3211 males). Their mean age was 41.68±0.17 years (M±SEM). At the time of this survey, all participants were residents of the Chelyabinsk region. General information was collected over the period from 06/01/2020 to 01/18/2022. Seropositivity for SARS-C0V-2 was assessed by test kits for IgG, IgM and IgA antibodies (JSC Vector-Best, Novosibirsk, Russia) against SARS-CoV-2 using “indirect” two-stage enzyme immunoassay (ELISA). Over the entire period, 27 cases were seronegative (20.45%); 99 samples were positive for IgA to SARS-CoV-2 (75%), and 6 samples (4.55%) yielded questionable ELISA results. IgG testing for SARS-Cov-2 antibodies was negative in 2433 cases (42.35%); 3245 samples (56.48%) were positive, and 67 specimens provided (1.17%) doubtful results using ELISA tests. IgM antibodies were not revealed in 2710 (70.41%) cases; 996 were positive (25.88%), and 143 specimens (3.72%) yielded doubtful results by ELISA technique. In general, the highest proportion of positive results was found in class A immunoglobulins. The wave-like distribution of the density among all antibody-positive patients was revealed, which, however, was not associated with peak values of COVID-19 morbidity in Chelyabinsk Region. Most waves of seroprevalence were detected before the waves of SARS-CoV-2 infection. A positive relationship was established between IgG and IgM seropositivity against SARS-CoV-2 with age and female gender. Conclusion. In general, serological testing and regular monitoring of antibodies against SARS-CoV-2 may play an important role in assessing its prevalence during the coronavirus pandemic and immune response to the infection at a population level.

Russian Journal of Immunology. 2022;25(2):219-226
pages 219-226 views

Effect of the KK1 peptide on immunological parameters in passively smoking pregnant rats and their offspring

Kuzmicheva N.A., Mikhailova I.V., Pushkareva L.A., Filippova Y.V., Bondarenko A.I., Sinegovets A.A., Smolyagin A.I.


Currently, experimental studies are actively conducted to assess the effects of low-molecular-weight polypeptide mediators on the immune system, in order to design new immunomodulatory drugs. However, the specific effects of individual peptides on the immune system of experimental animals and their offspring remains insufficiently studied, thus requiring relevant research in this aspect. Our study evaluated the effect of the peptide homologue of the of adrenocorticotropic hormone fragment (15-18) (laboratory code, KК1) on immunological parameters of pregnant rats and their offspring using experimental models of passive maternal smoking exposure.

The immunological parameters were studied in 96 pregnant Wistar rats weighing 200-300 g, exposed to passive tobacco smoking and receiving a synthetic peptide KK1, which is a structural analogue of the ACTH15-18 sequence fragment (Acetyl-(D-Lys)-Lys-Arg-Arg-amide), as well as probable effect on their offspring tested on the 14th day after birth (76 rats). Experimental rats were fumigated with tobacco smoke for 8 hours daily from the 1st to the 20th day of pregnancy. Synthetic peptide KK1 was administered to pregnant rats in the form of an aqueous solution at a dose of 40 mcg / kg / day five times a day for 10 days. Weights of whole body, thymus and spleen were determined in all animals, the number of leukocytes, thymocytes, splenocytes, myelocaryocytes, circulating immune complexes were assessed in accordance with common protocols for experimental laboratory animals. The data were analyzed by Mann–Whitney U test. The significance level was set at p < 0.05.

Administration of the KK1 peptide to both control and experimental pregnant rats was accompanied by multidirectional changes in the number of cells in lymphoid organs. The positive trend of shifts in immunological parameters when exposed to the peptide KK1 seems to be based on the possible reduction of the consequences of the toxic effect of tobacco smoke due to the anti-inflammatory effect of this drug, as well as its ability to limit the development of free radical reactions. It is shown that the studied peptide contributes to the positive dynamics of multiple immunological parameters in experimental animals subjected to passive smoking. Further studies are required to assess the mechanisms of immunotropic action of the ACTH15-18 peptide homologue.

Russian Journal of Immunology. 2022;25(2):227-234
pages 227-234 views

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